Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) have important nonhematopoietic roles in human developmental biology (Calhoun et al. [1999] (A) Pediatr Res 43:333–338; Tada et al. [1994] J. Neurosurg 80:1063–1073; McCracken et al. [1996] J Endocrinol 149:249–258; Ledbetter, D. J. et al. [2000] J. Pediatr Surg 35:178–182; Juul et al. [1998] Early Hum Dev. 52:235–249; Juul et al. [1999] (A) Pediatr Dev. Pathol 2:148–158). Among these roles, both G-CSF and Epo are trophic factors for the developing intestine (Juul et al. [1999] (B) Pediatr Res 46:263–8; and Gersting et al. [2000] Pediatr Res 47:287A).
The lumenal surface of the fetal and neonatal intestine is constantly exposed to G-CSF and Epo, since both are present in high concentrations in ingested fluids, including amniotic fluid, (Calhoun et al [1998] J Soc Gynecol Invest. 5:176A; Saito et al. [1992] Asia Oceania J Obstet Gynaecol 18:355–61; Clapp et al. [1995] Am J Obstet Gynecol 172 1445–51; Buescher et al. [1998] Int J Gynaecol Obstet 60: 257–263) colostrum, (Calhoun et al. [2000] Pediatrics 105:e7; Kling et al. [1998] Pediatr Res 43: 216–21) and milk (Calhoun et al. [2000] Pediatrics 105:e7; Kling et al. [1998] Pediatr Res 43: 216–21; Wallace et al. [1997] Br J Biomed Sci 54:87; Gilmore et al. [1994] Eur J Clin Nutr 48:222–4). Moreover, ingested G-CSF and Epo are highly protected from digestion in the neonatal intestine (Kling et al. [1998] supra; Wallace et al [1997] supra; Gilmore et al. [1994] supra; Calhoun et al. [1999] (B) Pediatr Res 46:767–71), and specific receptors for G-CSF and for EPO are expressed on the surface of fetal villous enterocytes (Calhoun et al. [1999] (A) supra; Juul et al. [1998] supra; Calhoun et al. [2000] supra). Animal studies and in vitro culture models indicate that binding of G-CSF and Epo to their cognate receptors on enterocytes results in trophic actions on villous height and bowel length (Juul et al. [1999] (B) supra; Gersting et al. [2000] supra; Juul et al. [2000] (A) Pediatr Res 47:289 A; and Juul et al. [2000] (B) Pediatr Res 47:165 A).
With preterm birth, the ingestion of amniotic fluid containing G-CSF, Epo, and other intestinal trophic factors ceases abruptly. It is often necessary in neonatology to withhold enteral feedings from extremely low birth weight (<1000 g) or preterm infants for days to weeks, relying exclusively, for that period of time, on parenteral nutrition (Giacoia et al. [1993] J Perinatol 13:297–9; Scholz et al. [1988] J Pediatr Gastroenterol Nutr 7:773–5; Schanler et al. [1999] Pediatrics 103:434–9; and Berseth et al. [1999] Front Biosci 4: d299–302). However, in such patients, villous atrophy occurs, and this likely predisposes them to feeding intolerance and necrotizing enterocolitis once feedings are instituted (Ledbetter et al. [2000] supra; Berseth et al. [1992] Pediatrics 90:669–73; Klurfeld [1999] Front Biosci4:D299–302; Mulvihill et al. [1 J Surg Res 40:291–6; Trahair [1995] J Pediatr Gastroenterol Nutr 20:156–61; and Karnak et al. [1996] Eur J Pediatr Surg 6:328–33).
Because the abrupt cessation in trophic factors swallowed in utero and the delay in receiving quantities of these growth factors in human milk likely result in villous atrophy and predispose preterm infants to feeding intolerance, it would be advantageous to provide low birth weight and/or preterm infants with critical intestinal trophic factors comparable to those they would have ingested from amniotic fluid had they remained in utero.